Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
Steroids. 2024 Dec;212:109521. doi: 10.1016/j.steroids.2024.109521. Epub 2024 Oct 10.
The central nervous system (CNS) is capable of synthesizing steroids for modulating essential functions such as neurotransmission, neuroplasticity, and neuroinflammation. These locally synthesized steroids, called neurosteroids, are produced through the conversion of cholesterol into the major steroid precursor pregnenolone, followed by downstream metabolism to form various steroids such as progesterone and allopregnanolone. Given that changes in neurosteroids are implicated in many neurological and psychiatric disorders, understanding the neurosteroidogenesis pathway is crucial. Recent studies have demonstrated an alternative pathway for the biosynthesis of pregnenolone, which is classically produced by CYP11A1 but was found instead to be made by CYP1B1 in human glial cells. However, numerous studies have demonstrated Cyp11a1 expression and activity in rodent brain tissue and brain cells. To elucidate whether species differences exist for the pregnenolone synthesis enzyme in human and rodent brains, we sought to directly compare the expression levels of CYP11A1 and CYP1B1 in human, rat, and mouse CNS tissues. We found that CYP1B1 mRNA expression was significantly higher than that of CYP11A1 in almost all CNS brain regions in human, rat, and mouse. The exception is in the mouse cerebral cortex, where Cyp11a1 RNA was more abundant than Cyp1b1. However, Cyp11a1 protein was clearly detectable in rodent CNS while completely undetectable in human brain. In contrast, the presence of CYP1B1 protein can be observed in both human and rodent brains. These results suggest that CYP1B1 is likely the dominant pregnenolone synthesis enzyme in the human brain, while rodent brains may use both Cyp11a1 and Cyp1b1.
中枢神经系统 (CNS) 能够合成类固醇，以调节神经传递、神经可塑性和神经炎症等基本功能。这些在局部合成的类固醇被称为神经甾体，它们是通过胆固醇转化为主要类固醇前体孕烯醇酮，然后进行下游代谢形成各种类固醇（如孕酮和别孕烯醇酮）而产生的。鉴于神经甾体的变化与许多神经和精神疾病有关，因此了解神经甾体的生物合成途径至关重要。最近的研究表明，孕烯醇酮的生物合成存在一种替代途径，经典途径是由 CYP11A1 产生的，但在人类神经胶质细胞中发现是由 CYP1B1 产生的。然而，许多研究表明 Cyp11a1 在啮齿动物脑组织和脑细胞中表达和具有活性。为了阐明人类和啮齿动物大脑中孕烯醇酮合成酶是否存在种属差异，我们试图直接比较 CYP11A1 和 CYP1B1 在人、大鼠和小鼠中枢神经系统组织中的表达水平。我们发现，在人类、大鼠和小鼠的几乎所有中枢神经系统脑区中，CYP1B1 mRNA 的表达水平均明显高于 CYP11A1。例外的是在小鼠大脑皮质中，Cyp11a1 RNA 比 Cyp1b1 更丰富。然而，Cyp11a1 蛋白在啮齿动物 CNS 中清晰可检测，而在人脑组织中则完全不可检测。相比之下，CYP1B1 蛋白存在于人和啮齿动物的大脑中。这些结果表明，CYP1B1 可能是人类大脑中孕烯醇酮的主要合成酶，而啮齿动物大脑可能同时使用 Cyp11a1 和 Cyp1b1。
